Elizabeth B. Robson

Two loci for Tuberous Sclerosis: one on 9q34 and one on 16p13

32 families informative for the segregation of Tuberous sclerosis (TSC) have been examined for genetic markers on chromosomes 9, 11, 12 and 16. In one large family there was clear evidence of linkage to markers on chromosome 16p13.3 (lodscore with D16S291 of 4·7 at θ= 0) but other families were too small to give individually convincing lodscores. Combined results for all families gave positive results with ABO/DBH on chromosome 9 (max lod 2·63) and with D16S291 on chromosome 16 (max lod 3·98) at values of theta of 0·2 in each case. Further analysis showed strong evidence for heterogeneity with approximately half the families linked to a locus TSC1 on chromosome 9 between ASS and D9S298 and half to TSC2 on chromosome 16 close to D16S291. There was no definite support for a third locus although in many families this could not be excluded. In three families the segregation pattern of TSC remains unexplained. In two of these the family apparently segregates for TSC1 but in each case a single affected individual appeared to exclude the whole of the candidate region. Preliminary analysis of clinical features did not reveal any definite differences in incidence of mental handicap between individuals in different linkage groups or with different sex of the parent of origin. The frequencies of periungual fibromas and facial angiofibromas were also similar in both linkage groups. The difficulties of detecting linkage in small families where there is locus heterogeneity are discussed. The program ZZ was found to be helpful in this respect.

The incidence of rare alleles determining electrophoretic variants: data on 43 enzyme loci in man

Inherited variants of many different enzymes have been discovered by electrophoretic techniques. In general they can be attributed to alleles which originated by mutation in individuals in earlier generations a t the loci coding for the structures of the particular enzymes. Population surveys indicate that such alleles vary very widely in their incidence, some being relatively common and others extremely rare. Up till now attention has mainly focused on the common alleles which give rise to the so-called enzyme polymorphisms. It has been found, for example, that polymorphism due to common alleles which determine electrophoretically distinct enzyme variants appears to occur in human populations at some 25-30% of loci coding for enzyme structure, and that the average heterozygosity per locus for such alleles is around 0.07 (Harris & Hopkinson, 1972). The same general phenomenon has of course also been demonstrated in a variety of other species and the recognition of its widespread occurrence has generated a great deal of discussion and not a little controversy about its fundamental biological significance. However, so far not much attention has been paid to relatively rare alleles which also give rise to electrophoretically detectable enzyme variants. This is no doubt, in part, because although many such variants have been reported, little systematic data on their incidence at different loci has been available. The purpose of the present paper is to present an extensive body of data which gives information about the incidence of such rare alleles over a wide range of loci. We believe that such data may provide an observational base which may help to extend the scope of current discussions about the nature and significance of enzyme polymorphism in particular, and about the character of enzyme diversity among the individual members of natural populations in general.

Birth weight in cousins.

There is a significant positive correlation between the birth weights of maternal first cousins, but not between other first cousins. This is interpreted as evidence for the existence of a maternal genetic factor in the determination of birth weight. Using estimates of the correlation between birth weight in sibs, twins and first cousins, the contribution to the total variance in birth weight of such factors as foetal genotype, maternal genotype and environment are discussed.

Further studies on the genetics of placental alkaline phosphatase

1. Six common and nine rare electrophoretically distinct phenotypes of human placental alkaline phosphatase are described.

PHENOTYPES AND GENOTYPES IN CYSTINURIA

Quantitative data are presented on the cystine, lysine and arginine excretion in patients with cystine stone formation and in their relatives in twenty‐five families.

Data on the incidence, segregation and linkage relations of the adenylate kinase (AK) polymorphism

Genetically determined variation in the enzyme adenylate kinase (AK) hm been described by Fildes 6 Harris (1966). About 90 yo of the English population were found to have an electrophoretic pattern designated AK 1, whilst 10 % had a different pattern, AK 2-1. Family studies showed that these phenotypes are determined by two autosomal alleles, AK1 and AK2, phenotype AK l corresponding to genotype AKlAKl and phenotype AK 2-1 to AK1AK2. The third phenotype, corresponding to the genotype AK2AK2, is relatively rare but has been observed both in the general population and in the offspring of AK 2-1 x 2-1 matings. These results have been confirmed by Bowman et al. (1967), who also described two unrelated examples of another phenotype referred to as AK 3-1. No family studies were performed in these cases. They also showed that in Negro populations the AK2 allele is very infrequent. In the present paper we shall give an analysis of routine AK typing on red cells from over 3000 individuals and of studies on 127 unselected families where one or both parents were of type AK 2-1.

THE PATTERN OF AMINO‐ACID EXCRETION IN CYSTINURIA

1. Cystine, lysine and arginine determinations have been carried out on urines from twenty‐eight cystinuric patients and 121 of their relatives. Urines from 250 unselected individuals have also been examined. The cystine was determined polarographically and the lysine and arginine microbiologically. The urines have also been examined for amino‐acids by two‐dimensional paper chromatography and by paper ionophoresis at pH 11‐5.

The CEPH consortium primary linkage map of human chromosome 10

The first CEPH consortium map, that of chromosome 10, is presented. This primary linkage map contains 28 continuously linked loci defined by genotypes generated from CEPH family DNAs with 37 probe and enzyme combinations. Cytogenetic localization of some of the genetic markers indicates that the consortium map extends, at least, from 10p13 to 10q26. The order of loci on the consortium map agrees with the physical localization data. The female map spans 309 cM (206 cM if an approximation of interference is included in the mapping function used to construct the map), and the mean genetic distance of intervals is 11 cM (7 cM). Also presented are maps of chromosome 10 from each of five CEPH collaborating laboratories, based on genotypes for all relevant markers in the CEPH database. The CEPH consortium map of chromosome 10 should be useful for localization of any gene of interest falling within the span covered. The genotypes in the chromosome 10 consortium map database are now available to the scientific community.

Genetically determined electrophoretic variants of human red cell NADH diaphorase.

Human red cell NADH diaphorase isozyme patterns have been examined in blood samples from 2783 unrelated individuals by starch gel electrophoresis. Most people exhibit a single banded isozyme pattern, designated phenotype Dia 1. Twenty‐nine people with variant isozyme patterns were encountered. Five different phenotypes (Dia 2‐1, 3‐1, 4‐1, 5‐1 and 6‐1) were identified, which from family studies appear to represent heterozygous combinations of one or other of a series of rare alleles (Dia2, Dia3, Dia4, Dia5 and Dia6) with a common allele (Dia1) at an autosomal locus.

Assignment of the human locus determining phosphoglycolate phosphatase (PGP) to chromosome 16

The segregation of human phosphoglycolate phosphatase has been studied in 52 independent human-rodent hybrids and 69 subclones. The results suggest that human PGP is on chromosome 16. Family data suggest that PGP is not close to 16qh or alpha Hp. The most likely regional assignment for PGP would appear to be 16p13 or 16p12, but a site on 16q cannot be entirely excluded. New data on 16qh and alpha Hp suggest that the male recombination fraction between these loci is about 0.2.